Cytochrome P450 inhibitors and uses thereof

Abstract

The present invention provides compounds having the general structural formula (I) (I) and pharmaceutically acceptable derivatives thereof, as described generally and in classes and subclasses herein, and additionally provides pharmaceutical compositions thereof, and methods for the use thereof for the treatment of any of a number of conditions or diseases involving fibrosis and proliferation, and where anti-fibrotic or anti-proliferative activity is beneficial.

What is claimed is: 
     
       1. A compound represented by Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         X is a triazole, which is optionally substituted with one or more independent R 5  substituents; 
         R 1  and R 2  are each independently lower alkyl; 
         A is 
       
       
         
           
           
               
               
           
         
       
       which is optionally substituted with one or more independent R 5  substituents;
 R 3  and R 4  are each independently hydrogen or lower alkyl; or R 3  with R 4 , taken together with the carbon atom to which they are attached, form a carbonyl or 3-10 membered saturated or unsaturated monocyclic or polycyclic ring, wherein said ring is optionally substituted with one or more R 5 ; 
 each occurrence of R 5  is independently hydrogen, halogen, cyano, hydroxy, nitro, —SO 2 NR 6 R 7 , —CONR 6 R 7  or NR 6 R 7 , haloalkyl, or lower alkyl group; and 
 R 6  and R 7  are each independently hydrogen or a lower alkyl group. 
 
     
     
       2. The compound of  claim 1 , wherein X is 1,2,4-triazole-4-yl. 
     
     
       3. The compound of  claim 1 , wherein X is 1,2,4-triazole-1-yl. 
     
     
       4. The compound of  claim 3 , wherein R 1  and R 2  are both ethyl. 
     
     
       5. The compound of  claim 4 , wherein R 3  and R 4  are each independently lower alkyl. 
     
     
       6. The compound of  claim 5 , wherein R 3  and R 4  are both methyl. 
     
     
       7. The compound of  claim 5 , wherein R 3  and R 4  are taken together with the carbon atom to which they are attached, form a 3-membered monocyclic ring. 
     
     
       8. The compound of  claim 5 , wherein R 3  and R 4  are taken together with the carbon atom to which they are attached, form a 4-membered monocyclic ring. 
     
     
       9. The compound of  claim 5 , wherein R 3  and R 4  are taken together with the carbon atom to which they are attached, form a 5-membered monocyclic ring. 
     
     
       10. The compound of  claim 5 , wherein R 3  and R 4  are taken together with the carbon atom to which they are attached, form a 6-membered monocyclic ring. 
     
     
       11. The compound of  claim 5 , wherein R 3  and R 4  are taken together with the carbon atom to which they are attached, form a 7-membered monocyclic ring. 
     
     
       12. A pharmaceutical composition comprising a compound of  claim 9  and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
       13. A method of treatment or lessening of the severity of a condition or disease associated with modulation of ATRA levels comprising administering to a subject in need thereof a compound of  claim 9  or a pharmaceutical composition thereof. 
     
     
       14. A method of treatment or lessening of the severity of a condition or disease associated with or characterized as cancer, emphysema, atherosclerosis, or neurological disorders comprising administering to a subject in need thereof a compound of  claim 9  or a pharmaceutical composition thereof. 
     
     
       15. A method of treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate fibrosis comprising administering to a subject in need thereof a compound of  claim 9  or a pharmaceutical composition thereof. 
     
     
       16. The method of  claim 15 , wherein the disease or condition is fibrotic liver disease; hepatic ischemia-reperfusion injury; cerebral infarction; ischemic heart disease; renal disease; pulmonary fibrosis; liver fibrosis associated with hepatitis C, hepatitis B, delta hepatitis, chronic alcoholism, non-alcoholic steatohepatitis, extrahepatic obstructions, cholangiopathies, autoimmune liver disease, and inherited metabolic disorders; damaged or ischemic organs, transplants or grafts; ischemia or reperfusion injury; stroke; cerebrovascular disease; myocardial ischemia; renal failure; renal fibrosis or idiopathic pulmonary fibrosis. 
     
     
       17. The method of  claim 15 , wherein the disease or condition is a wound; a damaged or ischemic organ, transplant or graft; ischemia or reperfusion injury in the brain, heart, liver, kidney, and other tissues and organs; myocardial perfusion as a consequence of chronic cardiac ischemia or myocardial infarction; vascular occlusion; ischemic tissues or organs; fibrotic diseases; hepatic disease; lung fibrosis; radiocontrast nephropathy; fibrosis secondary to renal obstruction; renal trauma and transplantation; renal failure secondary to chronic diabetes or hypertension; amyotrophic lateral sclerosis; muscular dystrophy; scleroderma; chronic obstructive pulmonary disease; diabetes mellitus; multiple sclerosis; trauma to the central nervous system; Parkinson's disease; Alzheimer's disease; and hereditary neurodegenerative disorders. 
     
     
       18. A method for treating a skin disease or disorder selected from actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyosis, keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus; glucocorticoid damage; age effects or damage; photo damage; and fine lines or wrinkles comprising administering to a subject in need thereof a compound of  claim 9  or a pharmaceutical composition thereof. 
     
     
       19. The method of  claim 18 , wherein the ichthyosis is ichthyosis vulgaris, lamellar ichthyosis, X-linked ichthyosis, congenital ichthyosiform erythroderma, epidermolytic hyperkeratosis, harlequin-type ichthyosis, ichthyosis bullosa of Siemens, ichthyosis hystrix, Curth-Macklin type, hystrix-like ichthyosis with deafness, lamellar ichthyosis, type 1, lamellar ichthyosis, type 2, lamellar ichthyosis, type 3 lamellar ichthyosis, type 4, lamellar ichthyosis, type 5, or autosomal recessive congenital ichthyosis. 
     
     
       20. A method of treatment or lessening of the severity of a condition or disease associated with or characterized by increased, excessive or inappropriate cellular proliferation comprising administering to a subject in need thereof a compound of  claim 9  or a pharmaceutical composition thereof. 
     
     
       21. The method of  claim 20 , wherein the condition or disease is cancer, psoriasis, an inflammatory joint disease or an inflammatory skin disease. 
     
     
       22. The method of  claim 20 , wherein the condition or disease is prostate cancer, breast cancer or ovarian cancer. 
     
     
       23. A method for inhibiting CYP26 in a subject comprising administering to said subject a compound of  claim 13  or a pharmaceutical composition thereof.